Viral infections are promptly recognized by host pattern recognition receptors (PRRs), such as Toll-like receptors (TLRs), RIG-I-like receptors (RLR) and many others, which activate cellular responses leading to production of type I interferons (IFN), proinflammatory cytokines and chemokines. This early cytokine response not only limits virus replication and spreading, but also orchestrates the onset of more specific and powerful adaptive immune response, which ultimately eliminates the viruses. The essential role of PRR-mediated innate cytokine response in defending viral infection is well illustrated by the fact that humans and mice deficient in the genes encoding PRRs or their signaling components are vulnerable to viral infections.
In order to establish infection, pathogenic viruses have evolved multiple mechanisms to evade and/or countermeasure PRR-mediated innate immune response. In fact, failure or improper activation of PRR-mediated cytokine response is frequently observed in many chronic viral infections, including chronic hepatitis B, for which the current antiviral therapy with viral DNA polymerase inhibitors fails to provide a cure.
Hepatitis B virus (HBV) is a non-cytopathic hepadnavirus that chronically infects more than 350 million people worldwide. Chronic hepatitis B virus (HBV) infection is due to the failure of a host to mount a sufficient immune response to clear the virus. The outcomes and pathogenesis of HBV infection are largely determined by the nature and magnitude of host antiviral immune response, which is generally related to the age at the time of infection. While over 95% of adult-acquired infections are spontaneously cleared within 6 months by a vigorous and polyclonal HBV-specific T cell response, more than 90% of exposed neonates and approximately 30% of children aged 1-5 years develop chronic infection, which is associated with a weaker and often barely detectable viral specific T cell response.
Sustained suppression of viral replication with long-term nucleos(t)ide analogue therapy or through a finite-duration of pegylated alpha interferon (IFN-α) therapy has been associated with improvement of liver diseases, prevention of liver decompensation and reduction of hepatocellular carcinoma morbidity and mortality. However, HBV surface antigen (HBsAg) seroconversion, the hallmark of a successful immunologic response to HBV with complete and durable control of infection, or a “functional cure,” is rarely achieved with the current therapies.
Although the antiviral efficacy of TLR and RLR agonists have been observed in HBV transgenic mice, as well as animals infected with WHV or DHBV, systemic administration of the PRR agonists in doses necessary to achieve antiviral effects is usually associated with significant adverse effects, due to the activation of a wide-spectrum of cellular response and massive production of pro-inflammatory cytokines.